Purpose: Activating mutations in AKT genes are rare but play an important role in the commonly dysregulated PI3K/AKT/mTOR signaling pathway. NCI-MATCH (EAY131) is a tumor agnostic platform trial that enrolled patients to targeted therapies based on matching tumor genomic alterations. Subprotocol Z1K evaluated ipatasertib, a pan-AKT inhibitor, in patients with AKT1E17K mutant metastatic tumors.
Methods: Patients received ipatasertib 400mg, orally once daily in a 28-day cycle until progression or unacceptable toxicity. Patients with known KRAS, NRAS, HRAS, or BRAF mutations were excluded. Prior PI3K and mTOR inhibitors were allowed. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), 6-month PFS, and toxicity.
Results: Thirty-five patients were enrolled, and 29 patients were included in the prespecified primary efficacy analysis. Multiple histologies were enrolled, with breast (n = 18) and gynecologic (n = 7) being the most common. The majority had > 3 lines of therapy (19/29, 65.5%). The ORR was 24.1% (7/29, 90% CI, 11.9%-40.6%) with P < 0.001 against a null rate of 5%. All responses were partial responses. Median response duration was 10.1 months (90% CI, 3.7-10.8). The most common toxicities of any grade included diarrhea (n = 25), nausea (n = 13), and hyperglycemia (n = 9). Grade 3/4 toxicities observed were consistent with reported toxicities for AKT inhibition. Twelve grade 3 events occurred that were thought to be at least possibly related to treatment.
Conclusions: The study met its primary endpoint with ipatasertib demonstrating clinically significant activity in heavily pretreated patients with various tumors harboring AKT1E17K mutations.